1. Field of the Invention
This invention is directed to an improved freeze-drying (lyophilization) process. More specifically, the instant invention concerns a freeze-drying process wherein cefazolin sodium for reconstitution for parenteral administration is prepared which is sterile, essentially amorphous and has good solubility characteristics on reconstitution with water for injection.
2. Prior Art
Freeze-drying is an old and often used process for removing a solvent from a solute. While the process is cumbersome, expensive and slow, it provides a method for removing a solvent without damaging heat labile solutes. Antibiotics and other pharmaceuticals have been processed by freeze-drying procedures for three or more decades and foods, particularly instant coffee, have been prepared by this method for many years. Ordinarily, a solution from which it is desired to recover the solute in a relatively solvent-free state is frozen solid and then subjected to an environment of a high vacuum and the temperature of the environment is raised to provide the units of heat absorbed in the sublimation of the solvent from the frozen solution. The temperature of the environment is kept below that which would result in the meltdown of the frozen solution. In practice, the temperature of the environment is coordinated with the vacuum to produce the highest reasonable sublimation rate, avoiding a melting of the frozen mass.
Water is the solvent generally utilized in a freeze-drying process. Other solvents can be employed but are limited to those which become solid in the range of temperatures which can be practically employed in the process and which will sublime under vacuum.
Although all of the material does not have to be in solution to effectively operate a freeze-drying process, instant coffee being one probable example, this invention is concerned with a process wherein amorphous material is prepared in a freeze-drying procedure from a true solution. In freeze-drying antibiotics and other pharmaceuticals it has been the practice to follow the classic process outlined above; to wit, prepare solution, freeze to solid, subject to high vacuum, add heat, sublime solvent. However, when such a conventional procedure is followed, some compounds come out as amorphous material, others as crystalline material, and still others as a mixture of amorphous and crystalline solids.
The cefazolin sodium involved in this invention can be prepared as crystalline material by utilizing a freeze-drying process such as that described in pending U.S. Patent application Ser. No. 567,224. The crystalline cefazolin sodium prepared by such process has good storage stability and pharmaceutical elegance. However, such cefazolin, while it is adequately soluble, as the sodium salt, in water for injection, is slow going into solution requiring as much as 21/2 minutes to dissolve 1.0g. in 2.5 ml of water with vigorous shaking at 25.degree. C.
Crystalline cefazolin sodium can also be recovered from organic solvents, such as ethanol. Such crystals require about the same amount of time to dissolve in water for injection as crystals obtained from a freeze-drying process.
It was found, quite surprisingly, that amorphous cefazolin sodium obtained by recovering such material from organic solvents by evaporating solutions of cefazolin sodium in such solvents to dryness could be dissolved in water for injection in about half the time required to obtain complete solutions of the crystalline material.
An approximate 50 percent reduction in the time required to effect the complete solutioning of cefazolin sodium comprises a significant improvement in that the time that a physician, nurse or paramedic would devote to the reconstitution of a vial of cefazolin sodium for parenteral administration would be substantially lessened, increasing the amount of time available for other activities.
However, utilizing amorphous cefazolin sodium recovered from solution by evaporating the solvent therefrom in sterile ampoule preparations for parenteral administration poses other problems and conditions which are both inefficient, difficult and costly. For example, there is no effective way known to sterilize amorphous cefazolin sodium recovered from a solution by evaporation so the entire process must be carried out in an aseptic environment. In the large and extensive process required to sterilely recover the cefazolin sodium there are many opportunities for the admittance of foreign substances into the material which later on will show up as suspended material in a reconstituted ampoule of the antibiotic. No one has yet developed an apparatus for filling dry material into an ampoule which will measure the material going into each ampoule with as good a consistency and precision as can be routinely achieved with liquid filling equipment.
Accordingly, it is an object of this invention to provide a process of freeze-drying cefazolin sodium that will result in sterile, essentially amorphous, cefazolin sodium for parenteral administration.
Another object of this invention is to provide a process which will include the filling of a measured volume of a sterile aqueous solution of a known concentration of cefazolin sodium into an ampoule wherein such cephalosporin is recovered from such solution as an essentially amorphous material for parenteral administration which is relatively rapidly soluble upon reconstitution with water for injection.
Still another object of this invention is to provide an ampoule containing an essentially amorphous cefazolin sodium which is storage stable and which upon reconstitution for parenteral administration is substantially free of foreign suspended material.